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Abstract: Acute Graft-Versus-Host Disease (aGVHD), mediated by CD4+ and CD8+ effector T cells, is a life-threatening complication in hematopoietic stem cell (HSC) transplantation. Naturally-occurring CD4+CD25hi(Foxp3+) regulatory T cells (Treg) have been shown to modulate tolerance to aGVHD in murine graft models. In this report, we investigated their role in the prevention of aGVHD in patients transplanted with bone-marrow-derived HSC. When CD4+CD25hiFoxp3+ T cells were isolated from bone-marrow grafts, they showed no suppressive activity. The analysis of their function in patients suffering from aGVHD after transplantation revealed a gain of suppressive activity indicating their inability to control the aGVHD induction. Thus, our findings clearly demonstrate that CD4+CD25+ and CD4+CD25hiFoxp3+ T cells, when administered in steady-state physiological conditions, do not influence the outcome of aGVHD after bone-marrow transplantation. [Copyright &y& Elsevier]

Acute graft-versus-host disease (aGVHD), mediated by CD4(+) and CD8(+) effector T cells, is a life-threatening complication in hematopoietic stem cell transplantation. CD4(+)CD25(hi) regulatory T cells (T(reg)) have been shown to modulate tolerance to aGVHD in murine models. Based on these observations, we examined their role in the prevention of aGVHD in patients who underwent transplantation with peripheral blood-mobilized hematopoietic stem cells after administration of granulocyte colony-stimulating factor. The effects of the G-CSF on the phenotype, frequency, and function of CD4(+)CD25(hi) T cells were analyzed in grafts and after transplantation to determine whether these cells were regulatory T cells. CD4(+)CD25(hi) T cells could be detected at the same frequency before and after granulocyte colony-stimulating factor administration in the donors' peripheral blood. The isolation of these cells from the grafts or from the recipients' peripheral blood after transplantation revealed that they were suppressive to the same extent as T(reg) isolated from healthy volunteers. Their number and frequency were estimated in the grafts and the results indicated that protection against aGVHD was not dependent on the T(reg) amount transferred to the recipients. Similarly there was no correlation between the number of circulating CD4(+)CD25(hi) T cells in the recipients' peripheral blood during the early period after transplantation and the outcome of aGVHD.